Premium
A Designed Conformational Shift To Control Protein Binding Specificity
Author(s) -
Michielssens Servaas,
Peters Jan Henning,
Ban David,
Pratihar Supriya,
Seeliger Daniel,
Sharma Monika,
Giller Karin,
Sabo Thomas Michael,
Becker Stefan,
Lee Donghan,
Griesinger Christian,
de Groot Bert L.
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201403102
Subject(s) - chemistry , conformational change , affinities , conformational ensembles , binding site , biophysics , plasma protein binding , population , binding affinities , protein structure , molecular dynamics , crystallography , stereochemistry , computational chemistry , biochemistry , biology , demography , receptor , sociology
In a conformational selection scenario, manipulating the populations of binding‐competent states should be expected to affect protein binding. We demonstrate how in silico designed point mutations within the core of ubiquitin, remote from the binding interface, change the binding specificity by shifting the conformational equilibrium of the ground‐state ensemble between open and closed substates that have a similar population in the wild‐type protein. Binding affinities determined by NMR titration experiments agree with the predictions, thereby showing that, indeed, a shift in the conformational equilibrium enables us to alter ubiquitin’s binding specificity and hence its function. Thus, we present a novel route towards designing specific binding by a conformational shift through exploiting the fact that conformational selection depends on the concentration of binding‐competent substates.